Method of making hydroxyquinone compounds



Patented Dec. 18, 1934 PATENT OFFICE,

, OUNDS Rudolph J. Anderson and Melvin S. Newman, New

HYDROXYQUINONE Haven, Conn., assignors to The New Haven Dispensary, New Haven, Conn., a corporation of Connecticut No Drawing. Application September 9,1933.

Serial No. 688,823 14 Claims. (01. 260

This invention relates to a hydroxyquinone and the method of making the same, and more particularly to a compound of this group having the formula CuHrOa.

, "Ihere occurs in human tubercle bacillus a yellow crystalline pigment which we have isolated for the first time in pure form andhave found to be of the above formula'.' Obtaining thissubstance from the human tubercle bacillus is a very expensive process, however, as itoccurs in only small quantities.

Hydroxyquinones in general possess interesting trolling or in alleviating tuberculosis, it has been deemed desirable to be able to produce such compounds by synthetic methods in order that they may be made available for experimental work. We have, therefore, devised a method of producing the substance above referred to by which it may be produced in quantity and at relatively small expense.

In the practice of our improved method we prefer to proceed in the following manner: A 2- methyl naphthalinis used as a starting material, and this 2-methyl naphthalin is oxidized with chromic acid in glacial acetic acid solution according to methods which are standard and which results in the formation of z-methyl-lA-naphthmquinone. The latter substance when crystallized from methyl alcohol is obtained as a lemon yellow crystalline product which has a melting point of approximately lot-106 centigrade.- This same quinone has been prepared and described by Fries hydride are boiled under a reflux condenser for a period of approximately one half hour. It will be understood that the portions of the various substances mentioned above are'those whichare gprefer'red, but we do :not limit ourselves precisely to the n oimts-stateinyrrne solution after it has been cooled to room temperature is decanted into cold water and the mixture is stirred untilv the acetic anhydride is decomposed. The diacetate which separates as a white solid is purified by crystallization from dilute methyl alcohol and is obtained in nearly quantitative yield in the form of colorless prismatic crystals which melt at approximately 114 centigrade. This same diacetate has been prepared previously by Fries and Lohmann and by others.

It is from this diacetate of 2-methyl-l,4-hydroxy naphthalin that we obtain the hydroxyquinone having the formula CiiI-IaOa. We have shown the chemical constitution of this substance probably to be 2-methyl-3-hydroxy-1,4-naphthoquinone, andto distinguish it we have given it the name phthiocol. In the reaction by which it is obtained from this diacetate, several by-products are formed so that the maximum yield of synthetic phthiocol is about 12% of the 20 are dissolved in about 50 parts of absolute ethyl alcohol and the solution is mixed with 100 parts of absolute ethyl alcohol containing a small quantity of any of the well-known alkalis, for example, containing about 2% of sodium ethoxide. Potassium or barium hydroxide could be used as well. The solution, which turns intensely dark red in color, is allowed to stand at room temperature for'a considerable period, approximately three hours, for example, after which it is diluted with water, acidified with a suitable acid such as hydrochloric acid or sulphuric acid and distilled with steam until the distillate is practically colorless. The distillate, which contains a yellow crystalline product, is extracted with ether. The ethereal extract is washed with water, after which it is shaken with a dilute hydroxide solution, such as a hydroxide solution of sodium or potassium. The alkaline solution turns deep red in color and contains thte alkali salt of the synthetic phthiocol, while the ethereal solution contains a neutral yellow crystalline compound.

f lhis red-alkaline solution is acidifiedjandjewtracted with ether. 7 The ethereal extract is below:'

'nmdmbkj-imthi te ydrow pm v arrying-.m' i-; .-q'u'r; invention a a nishi gain t ate: "and thatjconslderabla-modiil j -may be made, within the. spin 2 washed with water, dried over sodium sulphate, and evaporated to dryness when a yellow crystalline residue consisting of crude or somewhat impure phthiocol is obtained. For purification the crude product is dissolved in warm methyl alcohol and the solution is diluted with water until it turns slightly cloudy. As the solution cools, light yellow prismatic crystals separate, which are filtered ofi, washed with cold dilute methyl alcohol, and dried. This is the pure product having the formula CnHaOi, which we call phthiocol.

This substance is a yellow crystalline pigment which melts at approximately 173-174? centi grade, solidifies at 163 C.,-and remelts -a t 173- 174 C. It will be understood, of course, that the proportions of the various substances used in' the last reaction wherein the .new substance is obtained I droxynaphthalin are those which are preferred, but that departure may be made from theme of these exact proportions without departing from the spirit of the invention.

The steps involved in the manufacture of the substance, CuHaOa are shown by the formulas l Oxidation with l chromic d 2-methylnahpthalin .oqld a.

i ytrea ent' m nnu .51. The -method orj nyjiriiiimmne compo dj..which' Y comprise's thel'cxi'dation or. 2- methyl n'aphthali'n to formf 2.-'riiethyl1- 1,4-naph-1 'thoquinone;"and'the introduction of a hydroxyl "ring by the use of an oxidizing process.

group in the 3-position of the-l'A-naphthociuinone from the diacetateoi 2-methyl- 1,4hv

includes the step of treatment with an oxidizing agent.

3. The method of making a hydroxyquinone having the formula CiiHaOa which includes the step of the saponification and oxidation of diacetate of 2-methyl-1,4-hydroxynaphtha1in by treatment with an alkali.

4. The method of making a hydroxyquinone having the formula CuHaO: which includes the step of the sapo cation and oxidation of diacetate of 2-methyl-1,4-hydroxynaphthalin by treatment with an alkali in alcoholic solution.

5. The method of making a hydroxyquinone corhpound'which comprises the saponiflcation and oxidation of the diacetate of 2-methyl-l,4-hydroxynaphthalin with an alkali in alcoholic solu- '6.-The method of obtaining a substance having the formula Gill-i803 from the diacetate 01 2- methyl-Li-hydroxynaphthalin which comprises dissolving the latter in ethyl alcohol, mixing the solution with ethyl alcohol containing an alkali, and acidifying and distilling the mixture thus obtained. v

7. The method of making a hydroxyquinone compound which comprises preparing an alcoholic solutionof the'dia'cetate of 2-methyl-L4-hydroxynaphthalin and mixing said solution with ethyl alcohol fedntaining approximately 2% sodium e'thoxide, distilling the; solution thus obtained, and extracting the distillate withether.

I 8. The method of making a hydroxyquinone compound which comprises preparing an alcoholic' solution of the diacetate oi'2-methyl-1,4- hydroxynaphthalin and mixing said solution with ethyl alcohol containing approximately 2% sodium ethoxideacidiiymg and distilling the solution thus obtained, extracting the" distillate with I ether, treating the ethereal extract'with a dilute hydroxide solutiomand acidifying: the alkaline e method of niaking hydrox'yquinone ,robablyot the formula v wlivich 'comprises the step of oxidizing a hydroxyrobably of the formula which comprises the step of oxidizing a diacetate o! a hydroxy-alkylnaphthalinr 11. The method of making a hydroxyquinone probably of the formula which comprises the step of oxidizing the diacetate o! z-me hyl.

1-4 hydroxynaphthalin.

a hydroxyquinone methylnaph 13. Time method 01' making a hydroxyquinone probably of the formula v 10 which comprises the alkalizing of a diacetate of a droxy-methylnaphthalin.

14. The method compound which naphthoquinone to and the -subsequent; naphthalin.

reduction 01' a. form a. hydrownaphthalin 15 oxidation of the hydroxy- RUDOLPH J. ANDERSON. MELVIN s. NEWMAN. 

